Substituted 7-(1-alkoxy - 1 - alken-1-yl)-7,8-dihydro-6-methoxy-6,14-endo- (etheno or ethano) codides and morphides

ABSTRACT

THIS DISCLOSURES DESCRIBES COMPOUNDS OF THE CLASS OF SUBSTITUTED 7-(1-ALKOXY-1-ALKEN-1-YL)-7,8-DIHYDRO-6-METHOXY 6,14-ENDO- (ETHENO OR ETHANO) CODIDES AND MORPHIDES WHICH POSSESS ANALGESIC ACTIVITY.

United States Patent Office 3,560,505 Patented Feb. 2, 1971 U.S. Cl. 260285 10 Claims ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of substituted 7 l-al-koxyl-alkenl-yl) -7,8-dihydro-6-methoxy- 6,14-endo- (etheno or ethano) codides and morphides which possess analgesic activity.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of our copending application Ser. No. 671,106, filed Sept. 27, 1967. which is a continuation-in-part of our application Ser. No. 642,698, filed June 1, 1967, both now abandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel substituted 7-(l-alkoxy- 1 alken-1-yl)-7,8-dihydro-6-methoxy-6,l4-endo- (etheno or ethanol) codides and morphides and to methods of preparing these compounds. The novel compounds of the present invention may be represented by the following general formula:

Cl'IgO wherein R is hydrogen, lower alkyl or lower alkanoyl; R is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; R is hydrogen or alkyl of from 1 to 7 carbon atoms; R, is lower alkyl; and Y is etheno or ethano. Suitable lower alkyl and lower alkanoyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, formyl, acetyl, propionyl, isobutyryl, etc. Typical alkyl groups of from 1 to 7 carbon atoms are, for example, methyl, ethyl, n-propyl, n-butyl, isoamyl, sec.-hexyl, n-heptyl, etc. Suitable lower alkenyl groups are those having up to about 6 carbon atoms such as, for example, allyl, methallyl, dimethallyl, and the like. Suitable lower cycloalkylmethyl groups are those having from 4 to 7 carbon atoms such as cyclopropyl methyl, cyclobutylmethyl, cyclopentylmethyl, etc. Phenyl lower alkyl is exemplified by benzyl, u-phenylethyl, fi-phenylethyl, and the like.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are generally obtainable as crystalline materials having characteristic melting points and absorption spectra. They are appreciably soluble in many organic solvents such as ethanol, chloroform, benzene, ethyl acetate, and the like. They are, however, generally insoluble in water.

The organic bases of this invention form non-toxic acid-addition salts with a variety of organic and inorganic salt-forming agents. Thus, acid-addition salts, formed by admixture of the organic free base with the equivalent amount of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, citric, lactic, tartaric, acetic, gluconic, ascorbic, and the like. Also included within the purview of the present invention are the alkali metal salts (e.g., sodium and potassium) of the organic free bases when R in the above general formula is hydrogen. For purposes of this invention, the organic free bases are equivalent to their nontoxic acid-addition salts and their alkali metal salts.

The novel 7-(l-alkoxy-l-alkenyl-l-yl)-7,8-dihydro-6- methoxy-6,l4-endo- (etheno or ethano) codides and morphides (I) of the present invention may be readily prepared from an appropriately substituted 7-alkanoyl- 7,8-dihydro-6-methoXy-6,l4-endo- (etheno or ethano) codide (II) via a 7-[di(lower alkoxy)methyl] -7,8-dihydro- 6-methoxy-6,14-endo- (etheno or ethano) codide or morphide (III) in accordance with the following reaction scheme:

(1) Ketal forma- 0R4 naca c on.

(III) Additional transformations of R and/or N-R groups, when desirable COCHgRs wherein R R R R and Y are as hereinabove defined; R is hydrogen, cyano, propargyl, lower alkyl, lower alkenyl, phenyl lower alkyl or lower cycloalkylcarbonyl; R is similarly defined as R with the proviso that R may individually be a dilferent moiety from R R is similarly defined as R with the proviso that R, may individually be a different moiety from R R is hydrogen or lower alkanoyl when R is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; and wherein R is methyl when R is cycloalkylmethyl. By this procedure a 7-alkanoyl-7,8-dihydro-6-methoxy-6,14-endo- (etheno or ethano) codide (H) is converted to a suitable substituted 7- [di (lower alkoxy) methyl] -7,8-dihydro-6-methoxy-6, l4- endo- (etheno or ethano) codide or morphide (III) as described hereinbelow. These C-19 ketal derivatives (III; the C-19 carbon being bonded to the C-7 carbon) are then readily converted to the C-19 enol ethers of the present invention (I). One method by which this conversion is carried out is by heating the 0-19 ketals above their melting points. This reaction is carried out at from about 150 C. to about 250 C. A preferred temperature is about 200 C. This conversion is generally carried out in the absence of any solvent, and requires from a few minutes to an hour or more for substantial completion.

Inherent in the above described general preparative schemes for the novel compounds of the present invention are transformations of the 3-substitutent (R and/or transformations of the N-substitutent (R if required. For example, the 3-methoxy derivatives (codide series; I, R =CH may be transformed to 3-hydroxy derivatives (morphide series; IA; R =H) by heating with an alkali metal hydroxide in diethylene glycol. A particular advantage of this transformation is the fact that the C-19 e'nol ether moiety (in I) is unaffected during this reaction with alkali at an elevated temperature; these transformations are, therefore, included within the purview of the present invention. Similar treatment of C-7 ketones (such as H) with alkaline reagents has produced molecular rearrangements in which the 7-ketone group is altered. Thus, the alkaline transformation of a 3-alkoxy group to a 3-hydroxyl group in the presence of a C-19 enol ether, and the products produced therefrom, represent particularly desirable features of the present invention. This reaction is generally carried out at a temperature range of from about 150 C. to about 240 C., the range of from about 200 C. to about 220 C. being preferred. Heating is continued until the reaction is substantially complete, generally from about several minutes to several hours or more. Suitable metal hydroxides include potassium hydroxide, sodium hydroxide and the like. 3-alkanoyl morphides are obtained upon treatment of the above produced 3-hydroxy derivatives with alkanoic anhydrides such as acetic anhydride, propionic anhydride and the like, using) procedures well known to those skilled in the art.

Transformations of the N-substituent (R in I) are also useful methods for the compounds of this invention; and for certain examples are the preferred method of synthesis; these transformations are, therefore, included within the purview of the present invention. The N-methyl derivatives (codides and morphides; I, R =CH may be treated with cyanogen halides using procedures well known to those skilled in the art. N-cyano derivatives (IA, R7=CN) within the scope of this invention are thereby obtained. Hydrolysis of the N-cyano derivatives by heating with a metal hydroxide in diethylene glycol may then be employed to produce norcodides and normorphides (IA, R7=H). This procedure is particularly advantageous in that the C-19 enol ether moiety (in I) is unaffected by treatment with alkali at an elevated temperature. Similar treatment of C-7 ketones (such as II) with alkaline reagents has produced molecular rearrangements in which the C-7 ketone is a reactive moiety. Thus, the alkaline hydrolysis of an N-cyano group to an NH group in the presence of a C-19 enol ethers, and the products produced therefrom represent particularly desirable features of the present invention. This reaction is generally carried out at a temperature of from about C. to about 240 C., and the range of from about C. to about 180 C. is preferred.

In the preferred temperature range, hydrolysis of the N-cyano group proceeds readily without extensive transformation of a 3-methoxy group (if present). At higher temperatures, that is in the range of from about 200 C. to about 220 C., concomitant hydrolysis of both N-cyano and 3-methoxy groups takes place; this procedure which simultaneously transforms an N-cyano group and a 3-methoxy group is, therefore, the preferred method of synthesis for certain examples of this invention. Heating is continued until the reaction is substantially complete, generally from about several minutes to several hours or more. Suitable metal hydroxides in clude potassium hydroxide, sodium hydroxide, and the like. These norcodides and normorphides containing the secondary amine moiety are then realkylated with a suitable alkyl, cycloalkylmethyl, phenyl lower alkyl or propargyl halide or equivalent using procedures well known to those skilled in the art. Suitable alkylatiug agents include ethyl iodide, propargyl tosylate, benzyl chloride, phenethyl bromide, alkyl bromide, methallyl bromide, dimethallyl bromide and the like.

N-cycloalkylmethyl derivatives (IA, R =cyclopropylmethyl) are conveniently obtained from the nor-compounds by acylation with cycloalkylcarbonyl halides followed by reduciton with lithium aluminum hydride. Suitable reactants are cyclopropane-carbonyl chloride, cyclobutanecarbonyl bromide, and the like. Another especially desirable feature of the present invention is the fact that lithium aluminum hydride reduction of the cycloalkylcarbonyl amides (I, R =cyclopropylcarbonyl) proceeds readily, while the -19 enol ether moiety is unaffected. Similar reduction of N-cycloalkylcarbonyl groups in compounds containing a C-7 ketone group (i.e., II; R =cyclopropylcarbonyl and R =methyl) is not possible without concomitant reduction of the ketone.

The intermediate 7-[di(lower alkoxy)methyl]-7,8-dihydro-6-methoxy-6,l4-endo-(etheno or ethano) codides and morphides (III) may be readily prepared from an appropriately substituted 7 alkanoyl-7,8dihydro-6-methoxy-6,l4-endo- (etheno or ethano) codide (II) by treatment with a suitable acid and a lower alkanol (R OH), generally in the presence of its corresponding tri(lower alkyl)orthoformate ester [HC(OR (e.g., methanol and trimethyl orthoformate, ethanol and triethyl orthoformate, etc.). This reaction is conveniently carried out in an excess of the lower alkanol as the solvent, although in other cases an inert solvent such as benzene may be used. The preferred temperature range is from about 15 C. to about 100 C., over a period of time of from about several minutes to 24 hours or more. Suitable acids include, for example, perchloric acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, and the like. A preferred procedure is the reaction of the 7-alkanoyl derivative (II) with perchloric acid and the lower alkanol-tri (lower alkyl)orthoformate mixture (especially methanoltrimethyl orthoformate) at room temperature for about 5-10 minutes, at which time the transformation is substantially complete. The 7-alkanoyl-6-methoxy codides (II) required as starting materials are readily obtained as described by K. W. Bentley et al., J. Org. Chem. 23, 1925 (1958), and J. Am. Chem. Soc. 89, 3267, 3273 (1967).

The novel products of the present invention are useful and valuable intermediates for the preparation of a variety of novel compounds which possess analgesic and/or analgesic antagonist actions. One embodiment of this utility is the preparation of the novel substituted 7,8-di hydro-6-methoxy-6,l4-endo- (etheno or ethano) morphide-7-ketones and N-cycloalkylmethyl-7,8-dihydro-6- methoxy-6,14-endo- (etheno or ethano) norcodide-7- ketones (IV; wherein R is hydrogen or lower alkanoyl when R is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; and wherein R is methyl when R is cycloalkylmethyl), as illustrated in the above reaction scheme. This conversion of the appropriately substituted C-l9 enol ether derivative (IA) to C7 ketones (IV), which have been inaccessible by previously known methods, is readily accomplished by hydrolysis with dilute acid. Dilute aqueous acids including hydrochloric, sulfuric, phosphoric, trifiuoroacetic, and the like are generally used, and this transformation is substantially complete within a few minutes at room temperature. The temperature range is from about 0 C. to about C.

The novel 7-enol ethers (I) of the present invention and the 7-ketones (IV) derived therefrom are useful and valuable as analgesic agents which may show a variety of types of analygesic activity within the general scope of analgesic or antinociperceptive actions. These include morphine-like modes of action; nonnarcotic analgesic modes of action; and analgesic antagonist modes of action. The overall analgesic activity of a given compound within the scope of the present invention may be readily determined by applying one or more of. the routine tests described hereinbelow. The specific type of analgesic activity of a given compound may then be judged by those skilled in the art from the combined results of these several test procedures.

The novel compounds of the present invention are active analgesics when measured by the writhing syndrome test for analgesic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med., vol. 95, p. 729 (1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of one mg./kg. of body weight of phenyl-p-quinone in male Swiss albino mice weighing 1525 grams per mouse. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-p-quinone. The test compound is administered orally to groups of two mice each 30 minutes before injection of the phenyl-p-quinone. The total number of writhes exhibited by each group of mice is recorded for a 3 minute period commencing 15 minutes after injection of the phenyl-p-quinone. A compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of 18 or less. In a representative operation, and merely by way of illustration, 7a-(1-methoxyvinyl)- 6,7,8,l4-tetrahydro-6,l4-endoethenothebaine showed analgesic activity when tested by this procedure at an oral dose of 50 mg./kg. of body weight whereas 7a-acetyl- 6,7,8,l4 tetrahydro-6,l4-endoethenooripavine and 7aacetyl N cyclopropylmethyl 6,7,8,l4-tetrahydro-6,14- endoethenonororipavine both showed analgesic activity when tested by this procedure at an oral dose of 25 mg./ kg. of body weight. If desired, the median effective dose (ED for any particular compound may be calculated from the results obtained by repeating this test in multiple groups of two mice each at each of several graded dose levels.

A supplementary procedure which also indicates an analgesic mode of action is the rat tail-flick method described by F. E. dAmour and D. L. Smith, J. Pharmacol. Exptl. Therap., vol. 72, p. 74 (1941), with modifications. The compounds (generally as hydrochloride salts in 0.9% saline) are administered subcutaneously to groups of 5 rats each. Graded doses are given to several groups of rats. These rats are then individually subjected to the heat stimulus from a spot light lamp and a condensing lens focused on the blackened tip of the rat tail. The characteristic response to this presumably painful heat stimulus is to flick the tail out of the concentrated beam of the heat source. The response time (in seconds) is measured for control and treated groups, and the criterion of analgesia is approximately 100% increase in response time over controls. Established clinically active analgesics such as meperidine, codeine, morphine, etc., are active in the above test. When tested by this procedure, certain compounds of the present invention show this type of analgesic action. For example, 7u-(1-methoxyvinyl)-6,7,8, 14 tetrahydro-6,14-endoethenothebaine and 7a-acetyl- 6,7,8,l4-tetrahydro-6,14-endoethenooripavine show morphine-like analgesic activity when so tested at a dose of about one mg./kg. and 0.1 mg./kg., respectively, of body weight subcutaneously.

Additionally, supplementary routine tests known to those skilled in the art may be carried out to assess the importance of side effects frequently associated with the morphine-like analgesics. These include such actions as onset and duration of action, development of tolerance, respiratory depression, addiction liability, relative effects by oral and parenteral administration, and inhibitory effects on the gastrointestinal system.

Other compounds of this invention may show analgesic antagonist activity when tested against a selected dose of morphine or other morphine-like agents. This antagonist activity may be considered useful as a specific antidote for an overdose of a morphine-like agent, or for its nonnarcotic analgesic action. Experience has shown that such narcotic antagonists may also be capable of relieving pain despite the fact that they may be inactive in the rat tailflick procedure (see above), and have little or no addiction hazard; see L. S. Harris and A. K. Pierson, J. Pharmacol. Exptl. Therap., vol. 143, p. 141 (1964). Aanalgesics which produce satisfactory pain-relief without serious side effects, particularly with regard to the tolerance, habituation and drug dependence of the opiates, have been sought for many years. When tested against morphine by a procedure similar to that described by Harris and Pierson (supra), 7a-acetyl-N-cyclopropylmethyl-6,7,8,l4-tetrahydro-6,14-endoethenonorthebaine and 7a-acetyl-N-cyc1opropylmethyl-6,7,8,14 tetrahydro 6,14 endoethenonoroipavine both showed analgesic antagonist activity at a dose of about 2 mg./kg. and 0.03 mg./kg., respectively, of body weight subcutaneously.

In addition, supplementary test procedures such as measuring the elevation of the pain threshold of rat paws inflamed with brewers yeast may be carried out to confirm the analgesic action of the novel compounds of the present invention. In certain cases, these compounds also show antiinflammatory activity.

When mixed with suitable excipients or diluents, the compounds of this invention can be prepared as pills, capsules, tablets, powders, solutions, suspensions and the like for unit dosage, and to simplify administration. As analgesics they will relieve pain by direct action on the nerve centers or by diminishing the conductivity of the sensory nerve fibers. The novel compounds of the present invention may also be administered in combination therapy with salicylates such as aspirin and the like.

A preferred embodiment of the present invention consists of novel compounds which may be represented by the following general formula:

'Z-tertiary carbinols per K. W. Bentley et a1.

9 10 R R,o

N-R11-I ll IX so (VIII) case l R O-C= C-CHO 4 l R -n cm m l I N CH wherein R R R R and Y are as hereinabove de- 15 in an inert solvent such as methylene chloride, ethylene fined with the proviso that in the case of the 7-ketones chloride, chloroform, or an excess of the substituted (VII) when R is methyl then R is lower cycloalkylformamide employed to prepare the formylating reagent. methyl; and R is hydrogen, lower alkyl, phenyl, halo- The temperature range for the formylation reaction is phenyl, lower alkylphenyl, lower alkoxyphenyl or trifiuofrom about 0 C. to about 35 C. although room temromethylphenyl. Suitable lower alkyl and lower alkoxy perature is preferred. The hydrolysis step may be carried groups are those having from 1 to 4 carbon atoms such out with dilute acid or dilute alkali but preferably with as methyl, ethyl, isopropyl, n-butyl, methoxy, ethoxy, naqueous sodium acetate. When the formylation reaction propoxy, n-butoxy, etc. Suitable halophenyl groups are, is substantially complete (usually from several minutes for example, m-fiuorophenyl, p-chlorophenyl, m-chloroto several hours or more), the reaction mixture is stirred phenyl, m-bromophenyl, o-chlorophenyl, 2,5 dichlorowith aqueous sodium acetate for from several minutes to phenyl, 2,4,6-trichlorophenyl, 3,5-dichlorophenyl, 2,6-diseveral hours at room temperature and the product is isobromophenyl, pentafiuorophenyl, etc. Suitable low allated. The above described formylation reaction may be kylphenyl groups are, for example, p-tolyl, m-tolyl, o-tolyl, considered to be effected via a formylating reagent such p-ethylphenyl, p-isopropylphenyl, m-isobutylphenyl, etc. as that shown y compmlnd the tofmylatihg reagent ab e l er alkoxyphenyl groups are, for example, formed from N,N-dimethylformamide and phosgene. This m-methoxyphenyl, o-methoxyphenyl, m-ethoxyphenyl, pfofmylatihg reagent then reacts With isopropoxyphenyl, etc. \i/

In accordance with the above reaction scheme, a 7-[1,1- 9 f" di(lower alkoxy)alkyl]-7,8-dihydro-6-methoxy-6,14-endo- (C a)2N=CHCl-C1 R4OC:CCH=N(CHS)Z (etheno or ethano) codide or morphide derivative (VI) (X) (X1) is readily converted to the corresponding 7-(l-alkoxy-1- the 7'ehol ether to form an imhlhlm intermediate alken-l-yl)-7,8-dihydro-6-methoxy-6,14-endo (etheno or (P structure y Shown) Which is Converted ethano) codide or morphide derivative (V) of the presy hydrolysis to the 't y y derivaent invention by heating the 7-ketal derivative (VI) above tive its melting point. This reaction is carried out at from Subsequently, a y y y derivative about 150 C. to about 250 C. A preferred temperature (VIII) may be transformed to the Cofrfispohding is about 200 C. This conversion is generally carried out PY Y y' (etheIlO i th absence of any solvent, and requires f a few ethano) codide or morphide derivative (IX) by treatment minutes to an hour or more for substantial completion. f a hydrazine of the formula R13NHNH2- This Teacs b fl h 7 1 ether derivative (V) may he 4 tion is conveniently carried out in a solvent such as acetic dil transf r d to h ccrrcspcndihg 1 5 acid. The temperature range employed is from about dihydrohqhethoxyca14 chdo (etheno or ethano) codid,e C. to about 125 C. with the preferred range being from or hid d -i (VII) by hydrolysis With dilute 80 C. to 125 C. The reaction is conveniently carried out acid. Dilute aqueous acids including hydrochloric, sulby heating on the Steam bath or at the refluxing tempera f i phosphoric, t ifl i and the iike are 5 ture of the solvent, and is substantially complete within erally used, and this transformation is substantially com- 0 ttbout one hour to Several hours or 111011? All the P s plctc hi a few minutes at room temperature. The 1n the above reaction scheme are isolated and purified lk l derivatives (VII) may then be readily harm by standard procedures well known to those skilled in the formed to the corresponding 7-tertiary carbinols, a class of active analgesics, in accordance with the methods de- The Y yscribed by K W. Bentley et a1 Pros. Chem SOC 220 0 (etheno or ethano) codides and morphides (IX) are active 19 3 and J. Chem Soc 89, 3273, 3281 (1967) analgesics when measured by the writhing syndrome Further in accordance with the above reaction scheme, test, supra, for analgesic activity. In a representative opa 7-enol ether derivative (V) may be readily converted station and merely by Way of illustration, the following to the corresponding compounds are active analgesics when tested in this prohydro c mcthoxy 6,14 chdo (etheno or ethano) codide or cednre at the indicated oral dose as set forth in Table I morphide derivative (VIII) by treatment with a formylatbelow: ing agent followed by hydrolysis. In this case, the 7-enol TABLE I ether derivatives (V) may be isolated and purified or Oral dose. may be prepared in situ and formylated without isola- Compound of tion or purifiication depending upon the circumstances. 7 )odywelght The formyla'ting reagent is prepared by treating a sub- .'il li fft f ili fif fl ff ll 100 stituted formamide such as N,Ndimethylformamide, N,N- ;gi giiiig g'gigg i lf if 'tii g f m p t; 12 ehgiiiibflidlgiiiIifii-iiizifiydii'" 1118, y rmaml e, an t e like, with phos g {Ey 200 Phosphoryl chloride or thionyl chloride in an inert solfli dfiizlildfid t i fl 25 vent such as methylene chloride, ethylene chloride or 0 01 chloroform. Alternatively, an excess of the substituted i 't '9 formamide may be used as the solvent. The formylation tint ihiiiiiiiiiifitttffli? 0 004 reaction (V VIII) is also most convenently carried out ,ED50

When tested by the rat tail-flick procedure, supra using a high intensity heat stimulus calibrated to produce an average 46 second response time in untreated animals (controls), certain 7-(5-pyrazolyl) derivatives (IX) show this type of analgesic activity as indicated by the appropriate median effective doses as set forth in Table II below:

When tested by a procedure similar to that described by Harris and Pierson (above), N-cyclopropylmethyl-7a- (S-pyrazolyl)-6,7,8,14-tetrahydro 6,14 endoethenonorthebaine and N-cyclopropylmethyl-7a-(l-phenyl-S-pyrazolyl) 6,7,8,14 tetrahydro 6,14 endoethenonororipavine show analgesic antagonist actions when tested against morphine.

The novel compounds of this invention may exist in several isomeric forms such as stereoisomers. It is to be understood that the present invention includes within its scope all such isomeric forms. For example, the codides used as starting materials have several asymmetric carbon atoms, and epimers at the C7 asymmetric center are possible and are known. Formation of stereoisomers, or epimers, at C7 is therefore possible in the products of this invention. The nuclear magnetic resonance spectra of these 70rand 7B-(l-alkoxy-l-alken-l-yl)-7,8-dihydro-6- methoxy-6,14-endo-(etheno or ethano) codides and morphides are particularly helpful in characterizing the mixtures of epimers or the substantially pure stereoisomers as obtained from the reaction mixtures or from subsequent purifications and separations. These isomers may then be separated by methods (such as fractional crystallization and partition-chromatography) well known to those skilled in the art. In addition, cis-trans isomers are possible at the Cl9, 2O double bond. All such stereoisomeric forms of the 7-(l-alkoxy-l-alken-l-yl)-7,8-dihydro-6-methoxy-6,14-endo (etheno or ethano) codides and morphides are, therefore, included within the purview of this invention.

In accordance with accepted convention, an x-substituent at the 7-position is behind the plane of the paper whereas a fi-substituent at the 7-position is in front of the plane of the paper. This is usually represented by a bond for an OL-SlJbStltllCl'lt, a bond for a ,B-substituent, and a bond where both are indicated.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Preparation of 7u-(l-methoxyvinyl)-6,7,8,14-tetrahydro 6,14-endoethenothebaine 7a-(1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14- endoethenothebaine (250 mg.) is heated to 200 C. and kept at this temperature for 1 hour, the cooled melt is extracted with boiling n-hexane, and evaporation of the extract gives 7a-(1-methoxyvinyl)-6,7,8,14-tetrahydro- 6,14-endoethenothebaine as a glass (200 mg; 87%).

12 EXAMPLE 2 Preparation .of N-cyclopropylcarbonyl-72x-(l-methoxyvinyl) -6,7,8, 14-tetrahydro-6, 14-endoethenonorthebaine N-cyclopropylcarbonyl 7oz (1 dimethoxyethyl)- 6,7,8,14-tetrahydro-6,14-endoethenonorthebaine (50 mg.) is rapidly heated to about 210 C. The solid melts with effervescence, remains as a liquid for l0l5 minutes at ZOO-210 C., and then begins to solidify. Heating at 200- 210 C. is continued for about 15 minutes longer, the solid is cooled and collected with the aid of ether to give N-cyclopropylcar-bonyl 70c (1-methoxyvinyl)-6,7,8,14- tetrahydro-6,14-endoethenonorthebaine (27 mg.) M.P. 225-231 C.

EXAMPLE 3 Preparation of N cyclopropylmethyl-7a-(1-methoxy)- vinyl -6,7 ,8, 14-tetrahydro-6, 14-endoethenonorthebaine N-cyclopropylcarbonyl-7u-(l-methoxyvinyl) 6,7,8,14- tetrahydro-6,l4-endoethenonorthebaine (200' mg.) is added to a stirred suspension of lithium aluminum hydride (200 mg.) in anhydrous ether (10 ml.). The mixture is heated under reflux for 1 /2 hours and then decomposed with water. The ether solution is decanted, the residue is washed with ether, and the combined ether fractions are dried. Evaporation of solvent gives N-cyclopropylmethyl- 7a-(l-methoxyvinyl)-6,7,8,l4-tetrahydro 6,14 endoethenonorthebaine as an oil, showing nuclear magnetic resonance signals at 3.936 (=CH singlet 2H), 3.476 (C -OCH singlet, 3H), 2.356 (N-CH cyclopropyl; doublet, J =6 cps).

EXAMPLE 4 Preparation of 7a-( l-methoxyvinyl) -6,7,8,14-tetrahydro-6,14-endoethenooripavine 7u-(1-methoxyvinyl) 6,7,8,14 tetra'hydro-6,14-endoethenothebaine mg.) is added to a stirred solution of potassium hydroxide (740 mg.) in diethylene glycol (4 ml.) at ca. 210 C. The reaction mixture is stirred at ca. 210 C. for about 45 minutes, and then is cooled, diluted with water, and washed with ether. The aqueous solution is taken to pH 8 with saturated ammonium chloride solution added dropwise with stirring, and then is extracted with methylene chloride. The methylene chloride extract is washed with water, dried, and the solvent is evaporated to give 7a-(l-methoxyvinyl)-6,7,8,l4-tetrahydro-6,14-endoethenooripavine as a glass (101 mg),

k 290 mu, REES 298 mu EXAMPLE 5 Preparation of 7a-(l-methoxyvinyl)-6,7,8,l4-tetrahydro- 6,14-endoethenooripavine EXAMPLE 6 Preparation of 7oc-acetyl-6,7,8,14-tetrahydro-6,14- endoethenooripavine 7a-(l-methoxyvinyl)-6,7,8,14-tetrahydro 6,14 endoethenooripavine (ca. 75 mg.) is dissolved in dilute aqueous 'hydrochloric acid (5%) with slight heating. The acidic solution is allowed to stand at room temperature for 1 hour, and is then filtered from insoluble material, made basic with sodium bicarbonate, and extracted with methylene chloride. The methylene chloride extract is washed with water and dried. The residue obtained by evaporation of solvent is crystallized by trituration with ether and collected with the aid of hexane to give the crude product (28 mg). Recrystallization from methanol gives 70:- acetyl-6,7,8,14-tetrahydro-6,l4-endoethenooripavine, M.P. 212 C.2l4 C.

13 EXAMPLE 7 Preparation of N-cyano-7a-( l-methoxyvinyl) -6,7,8,14- tetrahydro-6,l4-endoethenonorthebaine Following the general procedure of Example 1, N- cyano-7a-(1,1-dimethoxyethyl) 6,7,8,14 tetrahydro- 6,l4-endoethenonorthebaine is heated above its melting point. Isolation of the product gives N-cyano-h-(l-methoxyvinyl)-6,7,8,14-tetrahydro 6,14 endoethenonorthebaine.

EXAMPLE 8 Preparation of 7a-(1-methoxyvinyl)-6,7,8,l4-tetrahydro- 6,14-endoethenonorthebaine Following the general procedure of Example 1, 7 u-( 1,1- dimethoxyethyl) 6,7,8,14 tetrahydro-6,14-endoethenonorthebaine is heated above its melting point. Isolation of the product gives 7u-(l-methoxyvinyl)-6,7,8,14-tetrahydro-6,l4-endoethenonorthebaine.

EXAMPLE 9 Preparation of N-al1yl-7a-( l-methoxyvinyl)-6,7,8,14-

tetrahydro-6, l4-endoethenonortheb aine Following the general procedure of Example 1, N-allyl- 7cc( 1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14-endoethenonorthebaine is heated above its melting point. Isolation of the product gives N-allyl-h-(Lmethoxyvinyl)-6,7,8,14-tetrahydro-6,14-endoethenonorthebaine.

EXAMPLE 10 Preparation of 7 a-( l-methoxyvinyl) -6,7,8, 14-tetrahydro- -6,14-endoethenonororipavine Following the general procedure of Example 1, 70a- 1,l-dimethoxyethyl)-6,7,8,14-tetrahydro 6,14 endoethenonororipavine is heated above its melting point for ca. 1 hour. Isolation of the product gives 7a-(1-methoxyvinyl) -6,7,8,14-tetra'hydro-6,14-endoethenonororipavine.

EXAMPLE 1 1 Preparation of 7 u-( l-methoxyvinyl)-N-propyl-6,7,8,14- tetrahydro-6,14-endoethenonorthebaine Following the general procedure of Example 1, 7a- 1,1-dimethoxyethyl)-N-propyl 6,7 ,8,14 tetrahydro-6,l4 endoethenonorthebaine is heated above its melting point. Isolation of the product gives 7a-(l-methoxyvinyl)-N- prowl-6,7,8, l4-tetrahydro-6, 14-endoethenonorthebaine.

EXAMPLE 12 Preparation of 7a-(1-methoxyvinyl)-N-phenethyl-6,7, 8,14-tetrahydro-6,l4-endoethenonorthebaine Following the general procedure of Example 1, 7a- (1,1-dimethoxyethyl) N phenethyl-6,7,8,l4-tetrahydro- 6,l4-endoethenonorthebaine is heated above its melting point. Isolation of the product gives 7a-( l-methoxyvinyl)- N-phenethyl-6,7,8,14-tetrahydro 6,14-endoethenonorthebaine.

EXAMPLE 13 Preparation of 7a-( l-methoxyvinyl) N (3 methyl-2- buten-l-yl)-6,7,8,14-tetrahydro 6,14 endoethenonorthebaine Following the general procedure of Example 1, 7a- (l,l-dimethoxyethyl) N propargyl 6,7,8,14-tetrahydro-16,l4-endoethenonorthebaine is heated above its 14 melting point. Isolation of the product give 7a-(1-methoxyvinyl) -N-propargyl 6,7,8,14 tetrahydro 6,14- endoethenonorthebaine.

EXAMPLE 15 Preparation of 7a-(l methoxy-l-buten-l-yl) 6,7,8,l4- tetrahydro-6,14-endoethenothebaine Following the general procedure of Example 1, 711- (1,1 dimethoxybutyl) 6,7,8,14 tetrahydro 6,14- endoethenothebaine is heated above its melting point. Isolation of the product gives 7a-(l-methoxy-l-butenl-yl)-6,7,8,14-tetrahydro-6,14-endoethenothebaine.

EXAMPLE 16 Preparation of 7a-(1-rnethoxyvinyl) 6,7,8,l4-tetrahydro- 6,14-endoethanothebaine Following the general procedure of Example 1, 711- (1,1 dimethoxyethyl) 6,7,8,l4 tetrahydro 6,14- endoethanothebaine is heated above its melting point. Isolation of the product gives 70: (1 methoxyvinyl)- 6,7,8,l4-tetrahydro-6,14-endoethanothebaine.

EXAMPLE 17 Preparation of 7a (l-n-propyloxyvinyl) 6,7 ,8,14- tetrahydro-6,14-endoethenothebaine Following the general procedure of Example 1, 7a-. (1,1 di -11 propyloxyethyl) 6,7,8,14 tethydro 6,14=

endoethenothebaine is heated above its melting point. Isolation of the product give 7a-(1-n-propyloxyvinyl)- 6,7,8,14-tetrahydro-6,14-endoethenothebaine.

EXAMPLE 18 Preparation of 7B-( l-methoxyvinyl)-6,7,8,l4-tetrahydro- 6,14-endoethenothebaine Following the general procedure of Example 1, 75- (1,1 dimethoxyethyl) 6,7,8,14 tetrahydro 6,14- endoethenothebaine is heated above its melting point. Isolation of the product gives 7/8- (1 -methoxyvinyl)- 6,7,8,14-tetrahydro-6,14-endoethenothebaine.

EXAMPLE 19 Preparation of 3-acetyl-7a-(l-methoxyvinyl)-6,7,8,14- tetrahydro-6, l 4-endoethenooripavine By treatment of 7a-(1-methoxyvinyl) -6,7,8,14-tetrahydro-6,l4-endoethenooripavine with acetic anhydride in pyridine, 3-acetyl-7a(1 methoxyvinyl) 6,7,8,l4-tetrahydro-6,l4-endoethenooripavine is thereby obtained.

EXAMPLE 20 Preparation of N-cyclopropylmethyl-h-(1-methoxyvinyl)- 6,7,8,14-tetrahydro-6,l4-endoethenonororipavine Following the general procedure of Example 1, N- cyclopropylmethyl 7a (1,1 dimethoxyethyl)-6,7,8,l4- tetrahydro-6,l4-endoethenonororipavine is heated above its melting point. Isolation of the product gives N-cyclopropylmethyl 7a (1 methoxyvinyl) 6,7,8,l4-tetrahydro-6,14-endoethenonororipavine.

EXAMPLE 21 Preparation of 7oc-( l-methoxy-l-buten-l-yl) -6,7,8, 14- tetrahydro-6,14-endoethenooripavine Following the general precedure of Example 1, 7o:- 1,1 dimethoxybutyl) 6,7,8,14 tetrahydro 6,14- endoethenooripavine is heated above its melting point. Isolation of the product gives 7a-(1-methoxy-l-buten-lyl)-6,7,8,14-tetrahydro-6,14-endoethenooripavine.

EXAMPLE 22 Preparation of N-allyl-7a-(1-methoxyvinyl)-6,7,8,l4- tetrahydro-6,14-endoethenonororipavine By reacting 7oz (1 methoxyvinyl) 6,7,8,l4-tetrahydro-6,14-endoethenonororipavine with allyl chloride in an inert solvent, N-allyl-7a-(l-methoxyvinyl)-6,7,8,14- tetrahydro 6,14 endoethenonororipavine is thereby obtained.

EXAMPLE 23 Preparation of N-cyano-7a-(-methoxyvinyl)-6,7,8,14- tetrahydro-6, l4-endoethenonorthebaine A solution of cyanogen bromide in chloroform is dried over sodium sulfate for a few minutes, and is then filtered onto 7a (1 methoxyvinyl 6,7,8,14 tetrahydro 6,14- endoethenothebaine, chloroform being used for washing. The mixture is heated under reflux. The cooled mixture is washed with an aqueous sodium bicarbonate solution, washed with water, and dried. The residue obtained by evaporation of the solvent is N-cyano-h-(l-methoxyvinyl) -6,7,8, l4-tetrahydro-6, 14-endoethenonorthebaine.

EXAMPLE 24 Preparation of 7a-( l-methoxyvinyl)-6,7,8,14-tetrahydro- 6,14-endoethenonorthebaine N -cyano 7a (l methoxyvinyl) 6,7,8,14 tetra hydro-6,l4-endoethenonorthebaine is added to a solution of potassium hydroxide in ethylene glycol heated to ca. 165 C. The reaction mixture is stirred at ca. 165 C. and is then cooled and diluted with water. The aqueous solution is extracted with diethyl ether, and the ether extracts are combined, washed with water and dried. The residue obtained by evaporation of the solvent is 70: (l methoxyvinyl) 6,7,8,14 tetrahydro 6,14- endoethenonorthebaine.

EXAMPLE 25 Preparation of N-allyl-7a-( l-methoxyvinyl) 6,7 ,8, 14- tetrahydro-6,14-endoethen0northebaine By reacting 7a (l methoxyvinyl) 6,7,8,l4-tethydro- 6,l4-endoethenonorthebaine with allyl bromide in an inert solvent, N allyl 7 7a (1 methoxyvinyl) 6,7,8,14- tetrahydro 6,14 endoethenonorthebaine is thereby obtained.

EXAMPLE 26 Preparation of N cyclopropylcarbonyl-7u-(1 methoxyvinyl) 6,7,8,14 tetrahydro 6,14 endoethenonorthebaine 7a (l methoxyvinyl) 6,7,8,14 tetrahydro 6,14- endoethenonorthebaine in pyridine is added dropwise to a stirred mixture of cyclopropylcarbonyl chloride and pyridine at 0 C., and the resulting mixture is stirred at 0 C. for ca. 2 hours. This is then added dropwise to an aqueous sodium bicarbonate solution with stirring. The precipitate is collected and dried in methylene chloride. The residue obtained upon evaporation of solvent is collected to give N-cyclopropylcarbonyl 70c (1 methoxyvinyl-6,7,8,14-tetrahydro-6,14-endoethenonorthebaine.

EXAMPLE 27 Preparation of N cyclopropylmethyl 7oz (l methoxyvinyl) 6,7,8,14 tetrahydro 6,14 endoethenonorthebaine tassium hydroxide in diethyleneglycol at ca. 21022U C. to give N-cyclopropylmethyl 7oz (1 methoxyvinyl)- 6,7,8,14-tetrahydro-6,14-endoethenonororipavine.

EXAMPLE 29 Preparation of N-(3-methyl-2-buten1-yl) -7a-( l-methoxyvinyl) -6,7,8,14-tetrahydro-6,14-endoethenonororipavine By reacting 7a-(1-methoxyvinyl)-6,7,8,l4 tetrahydro- 6,14 endoethenonororipavine with 3-methyl-2-buten-l-yl bromide in an inert solvent, N-(3-methyl-2-buten-1-yl)- 7a-(l-methoxyvinyl)-6,7,8,14-tetrahydro-6,l4 endoethenonororipavine is thereby obtained.

EXAMPLE 30 Preparation of N-cyclobutylcarbonyl-7w(l-methoxyvinyl) -6,7,8, 14-tetrahydro-6,14-endoethenonorthebaine Following the general procedure of Example 1, N-cyclobutylcarbonyl-7a-(1,1-dimethoxyethy1) -6,7,8,14 tetrahydro-6,14,-endoethenonorthebaine is heated above its melting point. Isolation of the product gives N-cyclobutylcarbonyl-7u-(1-methoxyvinyl)-6,7,8,l4 tetrahydro 6,14- endoethenonorthebaine.

EXAMPLE 31 Preparation of N-cyclobutylmethyl-h-(1-methoxyvinyl)- 6,7, 8,14-tetrahydro-6,14-endoethenonorthebaine Following the general procedure of Example 1, N-cyclobutylmethyl-7a-(1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14,-endoethenonorthebaine is heated above its melting point. Isolation of the product gives N-cyclobutylmethyl 7a (1 methoxyvinyl)-6,7,8,14-tetrahydro-6,l4-

r endoethenonorthebaine.

EXAMPLE 32 Preparation of N-cyclobutylmethyl-7a-(1-methoxyvinyl)- 6,7,8,14-tetrahydro-6,14-endoethenonororipavine Following the general procedure of Example 1, N-cyclobutylmethyl-7a-(1,1-dimeth0xyethyl) 6,7,8,14 tetrahydro-6,14-endoethenonororipavine is heated above its melting point. Isolation of the product gives N-cyclobutylmethyl-7a-(1-methoxyvinyl)-6,7,8,l4 tetrahydro 6,14- endoethenonororipavine.

EXAMPLE 33 Preparation of 7 ocl-methoxy-4-methyll-pentenl-yl) 6,7,8,14-tetrahydro-6,14-endoethenothebaine Following the general procedure of Example 1, 7u-(1,1- dimethoxy-4-methylpentyl) 6,7,8,14 tetrahydro 6,14- endoethenothebaine is heated above its melting point. Isolation of the product gives 7a-(1-methoxy-4-methyl-l-penten-1-yl)-6,7,8 ,l4-tetrahydr0-6,14-endoethenothebaine.

EXAMPLE 34 Preparation of 7ocl-methoxyvinyl) -6,7,8,14-tetrahydro- 6-14-endoethanooripavine Following the general procedure of Example 4, 7a-(1- methoxyvinyl) 6,7,8,14 tetrahydro-6,14-endoethanothebaine is treated with potassium hydroxide in diethylene glycol at ca, 210220 C. to give 7a-(1-methoxyvinyl)- 6,7,8,14-tetrahydro-6,l4-endoethanooripavine.

EXAMPLE 35 Preparation of N-cyano-7a-(l-methoxyvinyl)-6,7,8,14- tetrahydro-6, l4-endoethanonorthebaine Following the general procedure of Example 1, N- cyano-7a-(1,1-dimethoxyethyl)-6,7,8,14-tetrahydr0 6,14- endoethanonorthebaine is heated above its melting point. Isolation of the product gives N-cyano-7a-(1-methoxyvinyl) -6,7,8, l4-tetrahydro-6, 14-endoethanonorthebaine.

1 7 EXAMPLE 35 Preparation of 7a-( l-methoxyvinyl)-6,7,8,14-tetrahydro- 6, 14-endoethanothebaine Following the general procedure of Example 1, 7a-(l,ldimethoxyethyl)-6,7,8,l4 tetrahydro 6,14 endoethanothebaine is heated above its melting point. Isolation of the product gives 7a-(1-methoxyvinyl)-6,7,8,l4tetrahydro-6,14-endoethanothebaine.

EXAMPLE 37 Preparation of N-cyclopropylcarbonyl 70c (l-methoxyvinyl)-6,7,8, l4-tetrahydro-6, 1 4-endoethenonorthebaine N cyclopropylcarbonyl 7oz (1,1 dimethoxyethyl)- 6,7,8,14-tetrahydro-6,14-endoethanonorthebaine (50 mg.) is rapidly heated above its melting point. Heating is continued for about minutes longer, the solid is cooled and collected to give N-cyclopropylcarbonyl-h-(l-methoxyvinyl) -6,7,8,l4-tetrahydro-6,14-end0ethanonorthebaine.

EXAMPLE 38 Preparation of N-cyclopropylmethyl 7a (1 methoxyvinyl)-6,7,8, 14-tetrahydro-6,l4-endoethenonorthebaine N cyclopropylcarbonyl 70c (1 methoxyvinyl)- 6,7,8,14 tetrahydro-6,14-endoethanonorthebaine is added to a stirred suspension of lithium aluminum hydride in anhydrous ether. The mixture is heated under reflux for 1 /2 hours and then decomposed with water. The ether solution is decanted, the residue is Washed with ether, and the combined ether fractions are dried. Evaporation of solvent gives N-cyclopropylrnethyl 7oz (1 methoxyvinyl)-6,7,8,14-tetrahydro-6,14-endoethanonorthebaine.

EXAMPLE 39 Preparation of N-cyclopropylmethyl 7a (l-methoxyvinyl)-6,7,8,14-tetrahydrcr6,14-endoethenonororipavine Following the general procedure of Example 4, N-cyclopropylmethyl-7a-(l-methoxyvinyl) 6,7,8,14 tetrahydro- 6,14-endoethanonorthebaine is treated with potassium hydroxide in diethyleneglycol at ca. 210-220 C. to give N-cyclopropylmethyl-7a-( l-methoxyvinyl) 6,7,8,14 tetrahydro-6,14-endoethanonororipavine.

EXAMPLE 40 Preparation of 7a-( l-methoxyvinyl) -N- 3-methyl-2-buten- 1-yl)-6,7, 8,14-tetrahydro-6, 14-endoethanon0rthebaine Following the general procedure of Example 1, 7a-(l,1- dimethoxyethyl)-N-(3-methyl-2-buten-1-yl) 6,7,8,l4-tetrahydro-6,14-endoethanonorthebaine is heated above its melting point. Isolation of the product gives 7a-(1-rnethoxyvinyl)-N-(3-methyl-2-buten-l yl) 6,7,8,14 tetrahydro-6,14-endoethanonorthebaine.

EXAMPLE 41 Preparation of 706-( l-methoxyvinyl) -N- 3-methyl-2-butenl-yl)-6,7,8,14-tetrahydro-6,14-endoethanonororipavine Following the general procedure of Example 4, 7a-(1- methoxyvinyl) -N(3-methyl-2-buten-1-yl) -6,7,8,14 tetrahydro-6,14-endoethanonorthebaine is treated with potassium hydroxide in diethylene glycol at ca. 210220 C. to give 70: (l-methoxyvinyl)-N-(3-methyl-2-buten-1-yl)- 6,7,8,l4-tetrahydro-6,14-endoethanonororipavine.

EXAMPLE 42 Preparation of 7u-(l-methoxyl-1-buten-1-yl)-6,7,8,14- tetrahydro-6,14-endoethanothebaine Following the general procedure of Example 1, 7a-(l,ldimethoxybutyl)-6,7,8,14 tetrahydro 6,14 endoethanothebaine is heated above its melting point. Isolation of the product gives 7u-(l-methoxy-l-buten-l-yl) 6,7,8,14 tetrahydro-6,14-endoethanothebaine.

1 8 EXAMPLE 43 Preparation of 7fi-( l-methoxyvinyl)-6,7,8,14-tetrahydro- 6,14-endoethenooripavine Following the general procedure of Example 4, 7 3-(lmethoxyvinyl) 6,7,8,l4 tetrahydro-6,14-endoethenothe baine is treated with potassium hydroxide in diethylene glycol at ca. 210-220 C. to give 7B-(1-meth0xylvinyl)- 6,7, 8,14-tetrahydro-6,14-endoethenooripavine.

EXAMPLE 44 Preparation of N-cyano-7l3- l-methoxyvinyl)-6,7,8-14- tetrahydro-6,14-endoethenonorthebaine Following the general procedure of Example 1, N- cyano 7B (1,1 dimethoxyethyl)-6,7,8,l4-tetrahydro- 6,14-endoethenonorthebaine is heated above its melting point. Isolation of the product gives N-cyano-7j3-(lmethoxyvinyl) 6,7,8,14 tetrahydro 6,14-endoethenonorthebaine.

EXAMPLE 45 Preparation of 7B-(1-methoxyvinyl-)-6,7,8,14-tetrahydro- 6, 14-endoethenonorthebaine Following the general procedure of Example 1, 7 3-(l,ldimethoxyethyl) 6,7,8,14 tetrahydro-6,14-endoethenonorthebaine is heated above its melting point. Isolation of the product gives 7[3-(l-methoxyvinyl)-6,7,8-14-tetrahydro-6,l4-endoethenonorthebaine.

EXAMPLE 46 Preparation of N-cyclopropylmethyl-7B-(l-methoxyvinyl) -6,7,8, 14-tetrahydro-6, 14-endoethanonorthebaine pavine Following the general procedure of Example 4, N-cyclopropylmethyl 75 (l-methoxyvinyl)-6,7,8,14-tetrahydro-6,14-endoethenonorthebaine is treated with potassium hydroxide in diethyleneglycol at ca. 210-220 C. to give N-cyclopropylmethyl 7B (l-methoxyvinyl) 6,7,8,14- tetrahydro-6, 14-endoethenonororipavine.

EXAMPLE 48 Preparation of 7a-(1,l-dimethoxyethyl)-6,7,8,14-tetrahydro-6,14-endoethenothebaine Perchloric acid (20 ml.; 72%) is added dropwise to a stirred solution of 7ot-acetyl 6,7,8,14 tetrahydro-6,14- endoethenothebaine (40 g.) in methanol (400 ml.). Trimethyl orthoformate (200 ml.) is then added, and the mixture is stirred for 5 minutes. Pyridine (40 ml.) is then added, and the mixture is poured into aqueous sodium bicarbonate. The material which separates is collected and dissolved in methylene chloride solution, and this fraction is dried. Evaporation of solvent followed by crystallization from methanol gives 7a-(1,1-dimethoxyethyl) 6,7,8,-14 tetrahydro 6,14 endoethenothebaine (36.57 g.), M.P. 121-123 C. with effervescence. Second and third corps yield 2.1 g., M.P. 117-118 C. with effervescence and 0.6 g., M.P. *115-117 C. with effervescence.

EXAMPLE 49 Preparation of 7u-(1,l-dimethoxyethyl)-6,7,8,14-

tetrahydro-6,14-endoethenooripavine 7u-(1,1-dimethoxyethyl) 6,7,8,l4 tetrahydro 6,14- endoethenothebaine (5 g.) is added to a solution of potassium hydroxide (20 g.) in diethylene glycol ml.)

heated to ca. 210 C. The reaction mixture is stirred at ca. 210 C. for 25 minutes, and is then cooled and diluted with water. The aqueous solution is washed with ether, adjusted to pH 8 with ammonium chloride, and then extracted with methylene chloride. The methylene chloride extracts are combined, washed with water and dried. The oil obtained by evaporation of the solvent is crystallized from methanol (charcoal) to give 7a-(1,1-dimeth0xyethyl) 6,7,8,14 tetrahydro 6,14 endoethenooripavine (2.47 g.), M.P. 116-117 C. with effervescence. This material is solvated; when heated above its melting point, it resolidi-fies at about 135 C. and remelts at 178-180" C. A second crop (250 mg.) is also collected; M.P. 113- 114 C. with eflervescence, resolidified ca. 145 C., and remelts 174-176" C.

EXAMPLE 5 Preparation of N-cyano-7a-(1,1-dimethoxyethyl)- 6,7,8,14-tetrahydro-6,14-endoethenonorthebaine A solution of cyanogen bromide (17.9 g.) in chloroform (175 ml.) is dried over sodium sulfate for a few minutes and is then filtered onto 7ot-(l,1-dimethoxyethyl) 6,7,8,14 tetrahydro 6,14 endoethenothebaine (35 g.), chloroform (175 ml.) being used for washing. The mixture is heated under reflux for 26 hours. The cooled mixture is washed with an aqueous sodium bicarbonate solution, washed with water, and dried. The residue obtained by evaporation of the solvent is crystallized from methylene chloride-methanol to give N- cyano-7a-(1,1 dimethoxyethyl) 6,7,8,14 tetrahydro- 6,l4-endoethenonorthebaine (20 g.), M.P. 2112l4 C. with effervescence.

EXAMPLE 51 Preparation of 7a-(1,1-dimethoxyethyl)-6,7,8,14- tetrahydro-6, l4-endoethenonorthebaine N-cyano 70c (Ll-dimethoxyethyl) 6,7,8,14 tetrahydro 6, 14 endoethenonorthebaine (0.5 g.) is added to a solution of potassium hydroxide (2 g.) in ethylene glycol (10 ml.) heated to ca. 167 C. The reaction mixture is stirred at ca. 167 -C. for 15 minutes, and is then cooled and diluted with water. The aqueous solution is extracted with diethyl ether, and the ether extracts are combined, Washed with water and dried. The residue obtained by evaporation of the solvent is crystallized from diethyl ether to give 7a-(1,l-dimethoxyethyl)-6,7,'8,14- tetrahydro-6,1 4-endoethenonorthebaine (213 mg.), M.P. 139145 C.

EXAMPLE 52 Preparation of N-allyl-7a-(1,l-dimethoxyethyl)-6,7,8,l4- tetrahydro-6,14-endoethenonorthebaine EXAMPLE 5 3 Preparation of 7m-(1,l-dimethoxyethyl)-6,7,8,14-tetrahydro-6, l4-endoethenonororipavine One hundred ml. of diethylene glycol containing 20.0 g. potassium hydroxide is heated to 215 C. and 5.00 g. of 7a-(1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14- endoethenonorthebaine is added. The temperature is maintained between 215 C. and 220 C. for 30 minutes and then allowed to cool to room temperature over about one hour. The solution is diluted with 200 ml. of water, and ml. of saturated aqueous ammonium chloride is added. The solution is extracted with six 50 ml. portions of methylene chloride which are combined, extracted one time with water, dried over anhydrous sodium sulfate and evaporated to give an oil which crystallizes upon trituration with methanol; 7u(1,1dimethoxyethyl)- 6,7,8,14 tetrahydro-6,14-endoethenonororipavine, M.P. 260 C. decomp. is obtained.

EXAMPLE 54 Preparation of 3-acetyl-7a-( l, l-dimethoxyethyl) -6,7,8,14- tetrahydro-6,14-endoethenooripavine By treatment of 7a-(1,l-dimethoxyethyl)-6,7,8,14-tetrahydro-6,l4-endoethenooripavine with acetic anhydride in pyridine, 3-acetyl-7a-( 1,1-dimethoxyethyl)-6,7,8,14-tetrahydro-6,14-endoethenooripavine is thereby obtained.

EXAMPLE 55 Preparation of 7a-(1,1-dimethoxyethyl)-Npropyl-6,7,8, 14-tetrahydro-6,14-endoethenonorthebaine By reacting 70c (1,l-dirnethoxyethyl)-6,7,8,14-tetrahydro 6,14-endoethenonorthebaine with propyl iodide in an inert solvent, 7a-(1,l-dimethoxyethyl)-N-propyl-6,7,8,l4- tetrahydro-6,14-endoethenonorthebaine is thereby obtained.

EXAMPLE 56 Preparation of 7u-(1,l-dimethoxyethyl)-N-phenethyl-6,7, 8,14-tetrahydro-6,14-endoethenonorthebaine By reacting 7a-(1,1-dimethoxyethyl)-6,7,8,14-tetrahydro-6,14-endoethenonorthebaine with phenethyl bromide in an inert solvent, 7a-(1,l-dimethoxyethyl)-N-phenethyl- 6,7,8,14-tetrahydro-6,14-endoethenonorthebaine is thereby obtained.

EXAMPLE 57 Preparation of 7 u-(1,1-dimethoxyethyl)-N-(3-methyl-2- buten-l-yl)6,7,8,14-tetrahydro 6,14 endoethenonorthebaine 7a (Ll-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14- endoethenonorthebaine (4.135 g.) is dissolved in ethanol (50 ml.) containing sodium carbonate (5 g.), l-bromo-3- methyl-2-butene (dimethyallyl bromide) (5 ml.) is added, and the mixture refluxed one hour. After cooling and rflltration the solution is evaporated to give a semicrystalline mass with a carbonyl band in the infrared spectrum at 5.75 indicating the presence of ketone (from hydrolyzed ketal). This material is dissolved in methanol (50 ml.) and 70% perchloric acid (2.5 ml.) added followed by trimethylorthoformate (25 ml.). After stirring five minutes at room temperature, pyridine (5 ml.) is added and the entire solution then poured into aqueous saturated sodium bicarbonate solution ml.). An oil separates, and the remaining aqueous solution is extracted three times with 50 ml. portions of methylene chloride. The methylene chloride extracts contained no significant amount of material (weight and infrared spectrum) and is discarded. The oil is taken up in methylene chloride, dried over sodium sulfate and evaporated to give a darkyellow glass (no ketone band by infrared). This crude product, 7a-(1,1-dimethoxyethyl) N (3-methyl-2-buten-l-yl)6,7,8,14-tetrahydro 6,14 endoethenonorthebaine, is then used for subsequent reactions without further purification.

EXAMPLE 58 Preparation of 7oz-(l,l-dimethoxyethyl)-N-propargyl-6,7, 8, 14-tetrahydro-6,14-endoethenonorthebaine by obtained.

21 EXAMPLE 59 Preparation of 7a-(1,1-dimethoxybutyl)-6,7,8,14-tetrahydro-6,14-endoethenothebaine Following the general procedure of Example 48, 7abutyryl-6,7,8,14-tetrahydro 6,14 endoethenothebaine is treated with perchloric acid and trimethyl orthoformate in methanol at room temperature to give 7 a-(1,1-dimethoxybutyl)-6,7,8,14-tetrahydro-614,-endoethenothebaine.

EXAMPLE 60 Preparation of 7a-(1,1-di-n-propyloxyethyl)-6,7,8,14- tetrahydro-6,14-endoethenothebaine Following the general procedure of Example 48, 7aacetyl 6,7,8,14 tetrahydro-6,14-endoethenothebaine is treated with perchloric acid and tri-n-propyl orthoformate in n-propanol at room temperature to give 7a-(1,1-di-npropyloxyethyl) 6,7,8,14 tetrahydro-6,14-endoethenothebaine.

EXAMPLE 61 Preparation of 7a-(1,l-dimethoxybutyl)-6,7,8,14-tetrahydro-6,14-endoethenooripavine Following the general procedure of Example 49, 70:- (1,1 dimethoxybutyl) 6,7,8,14 tetrahydro-6,14-endoethenothebaine is treated with potassium hydroxide in di ethylene glycol at ca. 210-220 C. to give 7a-(1,1-dimethoxybutyl) 6,7,8,14 tetrahydro-6,I l-endoethenooripavine.

EXAMPLE 62 Preparation of N-cyclopropylcarbonyl-7a-(1,1-dimethoxyethyl) -6,7,8,14-tetrahydro-6,14-endoethenonorthebaine 7a (1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14- endoethenonorthebaine (50 mg.) in pyridine (2 ml.) is added dropwise to a stirred mixture of cyclopropylcarbonyl chloride (50 mg.) and pyridine (2 ml.) at C., and the resulting mixture is stirred at 0 C. for ca. 2 hours. This is then added dropwise to an aqueous sodium bicarbonate solution with stirring. The precipitate is collected and dried in methylene chloride. The residue obtained upon evaporation of solvent is collected with diethyl ether to give N-cyclopropylcarbonyl-7u-(1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14-endoethenonorthebaine (30 mg), M.P. 164-169 C. with effervescence.

EXAMPLE 63 Preparation of N-cyclopropylmethyl-7 x(1,1-dimethoxyethyl)-6,7,8,14-tetrahydro-6,14-endoethenonorthebaine Finely powdered N cyclopropylcarbonyl-7a-(1,1-dimethoxyethyl) 6,7,8,14 tetrahydro-6,14-endoethenonorthebaine (51.5 g.) is added to a stirred suspension of lithium aluminum hydride (26 g.) in diethyl ether (2 liters) and the mixture is heated under reflux for 2 hours. Water is added dropwise cautiously until the excess of lithium aluminum hydride decomposes and then the ether is decanted and dried. The residue obtained by evaporation of solvent is crystallized from methanol-n-hexane to give N-cyclopropylmethyl-7a-(1,1 dimethoxyethyl)-6,7, 8,14-tetrahydro 6,14 endoethenonorthebaine (41.86 g., 83.5%), MP. 130132 C.

EXAMPLE 64 Preparation of N-cyclopropylmethyl-7a-(1,1-dimethoxyethyl) 6,7,8, 14-tetrahydro-6, l4-endoethenonororipavine Following the general procedure of Example 49, N- cyclopropylmethyl 7a(1,1 dimethoxyethyl) 6,7,8,14- tetrahydro-6,14-endoethenonorthebaine (2 g., 4.3 mmole) is added to a stirred solution of potassium hydroxide (8 g.) in diethylene glycol (40 ml.) at ca. 220 C. After 30 minutes at this temperature the mixture is cooled and diluted with Water. The solution is adjusted to pH 8 with saturated aqueous ammonium chloride added dropwise with vigorous stirring. The precipitate which forms is filtered off and dried via methylene chloride solution. The oil obtained by evaporation of the solvent is treated with charcoal in diethyl ether solution. Evaporation of solvent gives an oil which crystallizes from methanol to give N- cyclopropylmethyl 7a (1,1 dimethoxyethyl) 6,7,23,14- tetrahydro 6,14 endoethenonororipavine methanolate, M.P. 97-99 C. with elfervescence.

EXAMPLE Preparation of N-cyclobutylcarbonyl-7a-(1,1-dimethoxyethyl)-6,7,8,14-tetrahydro-6,l4-endoethenonorthebaine Cyclobutylcarbonyl chloride (10 g.) is added to methylene chloride (200 ml.) containing anhydrous potassium carbonate (10 g.) and stirred at room temperature for 15 minutes. The ketal 7a (1,1 dimethoxyethyl)-6,7,8,14- tetrahydro 6,14 endoethenonorthebaine (20 g. in methylene chloride (200 ml.) is added in a rapid stream, and the mixture stirred for one hour. After washing with excess aqueous sodium bicarbonate solution and then with water the organic solution is dried over sodium sulfate and evaporated to give an oil (a band in the infrared at about 6.7 indicates the presence of ketone from hydrolized ketal). The oil is then dissolved in methanol (200 1111.), 72% perchloric acid (10 ml.) is added followed by trimethylorthoformate ml.). After stirring at room temperature for five minutes, pyridine *(20 ml.) is added and the entire mixture poured into aqueous sodium bicarbonate solution (300 ml.). The mixture is extracted six times with 50 ml. portions of methylene chloride; the organic phases are combined, extracted with water, dried over sodium sulfate and evaporated. Crystalline N-cyclobutylcarbonyl 7a-(1,1 dimethoxyethyl) 6,7,8,l4-tetrahydro- 6,14 endoethenonorthebaine is obtained in 5 successive crops by crystallization from methanol/ hexane (total yield 17.15 g.; 71.5%), M.P.184- C.

EXAMPLE 66 Preparation of N-cyclobutylmethylJw(1,1-dimethoxyethyl)-6,7, 8,14-tetrahydro-6, 14-endoethenonorthebaine N-cyclobutylcarbonyl 7a (1,1 dimethoxyethyl) 6, 7,8,l4-tetrahydro-6,14-endoethenonorthebaine (16.4 g.) is mixed with 200 ml. of diethyl ether and added to a'stirred suspension of lithium aluminum hydride (7 g.) in 400 ml. of diethyl ether, and the mixture is heated under reflux for 2.5 hours. Water is cautiously added dropwise until the excess lithium aluminum hydride is decomposed. The ether layer is decanted, dried, and evaporated to a noncrystalline residue. N-Cyclobutylmethyl 7oz (1,1 dimethoxyethyl) 6,7,8,l4 tetrahydro 6,14 endoethenonorthebaine is thereby obtained as a glass; infrared, no carbonyl band; nuclear magnetic resonance 5 3.22 (C dimethoxy) and 2.50 (NCH C H EXAMPLE 67 Preparation of N-cyclobutylmethyl-7a-1,ldimethoxyethyl)-6,7,8,14 tetrahydro-6,14-endoethenonororipavine Following the general procedure of Example 49, N- cycylobutylmethyl 7a-(1,l dimethoxyethyl) 6,7,23,14- tetrahydro-6,I l-endoethenonorthebaine is treated with potassium hydroxide in diethyleneglycol at ca. 210220 C. to give N cyclobutylmethyl-7a(l,l-dimethoxyethyl)-6,7, 8,14-tetrahydro-6,14-endoethenonororipavine.

EXAMPLE 68 Preparation of 7a-(1,1-dimethoxy-4-methylpentyl)-6,7,8, 14-tetrahydro-6,14-endoethenothebaine Following the general procedure of Example 48, 7a-(4- methylpentanoyl) 6,7,8,14 tetrahydro 6,14 endoethenothebaine is treated with perchloric acid and trimethyl orthoformate in methanol at room temperature to give 70:- (l,1 dimethoxy 4 methylpentyl) 6,7,8,14 -tetrahydro- 6,14-endoethenothebaine.

23 EXAMPLE 69 Preparation of 7oa-(1,1-dimethoXyethyl)-6,7,8,14-tet1ahydro-6,14-endoethanothebaine Following the general procedure of Example 48, 7aacetyl 6,7,8,14 tetrahydro-6,14-endoethanothebaine is treated with perchloric acid and trimethyl orthoformate in methanol at room temperature to give 7oc-( 1,1-dimethoxyethyl) -6,7, 8,14-tetrahydro-6,14-endethanothebaine.

EXAMPLE 70 Preparation of N-cyano-7a-( 1, l-dimethoxyethyl) -6,7,8,14- tetrahydro-6,14-endoethanonorthebaine A solution of cyanogen bromide in chloroform is dried over sodium sulfate for a few minutes, and is then filtered onto 7oz (1,1-dimethoxyethyl)-6,7,8-14-tetrahydro-6,14- endoethanothebaine, chloroform being used for washing. The mixture is heated under reflux for about 24 hours. The cooled mixture is washed with an aqueous sodium bicarbonate solution, washed with water, and dried. The residue obtained by evaporation of the solvent is crystallized to give N-cyano-7a-(1,l-dimethoxyethyl)-6,7,8,14- tetrahydro-6,14-endoethanonorthebaine.

EXAMPLE 71 Preparation of 7ot-(1,1-dimethoxyethyl) -6,7,8,l4-tetrahydro-6,14-endoethanonorthebaine N cyano 7a (1,1 dimethoxyethyl)-6,7,8,l4-tetrahydro-6,14-endoethanonorthebaine is added to a solution of potassium hydroxide in ethylene glycol heated to ca. 165 C. The reaction mixture is stirred at ca. 165 C. for 15 minutes, and is then cooled and diluted with water. The aqueous solution is extracted with diethyl ether, and the ether extracts are combined, washed with water and dried. The residue obtained by evaporation of the solvent is crystallized to give 7a-(1,l-dimethoxyethyl)-6,7,8,14- tetrahydro-6,14-endoethanonorthebaine.

EXAMPLE 72 Preparation fo N-cyclopropylcarbonyl-7a-( 1,1-dimethoxyethyl) -6,7,8, 14-tetrahydro-6, 14-endoethanonorthebaine 70c (1,1-dimethoxyethyl) 6,7,8,14 tetrahydro 6,14- endoethanonorthebaine in pyridine is added dropwise to a stirred mixture of cyclopropylcarbonyl chloride and pyridine at 0 C., and the resulting mixture is stirred at 0 C. for ca. 2 hours. This is then added dropwise to an aqueous sodium bicarbonate solution with stirring. The precipitate is collected and dried in methylene chloride. The residue obtained upon evaporation of solvent is collected with diethyl ether to give N-cyclopropylcarbonyl 7a-(1,1-dimethoxyethyl) 6,7,8,14-tetrahydro-6,14-endoethanonorthebaine.

EXAMPLE 73 Preparation of 7 oz (1,1 dimethoxyethyl)-N-3-methyl-2- buten 1 yl)-6,7,8,14-tetrahydro-6,14-endoethanonorthebaine By reacting 7a (1,1 dimethoxyethyl) 6,7,8,14-tetrahydro 6,14-endoethanonorthebaine with 3-methyl-2-buten-l-yl bromide in an inert solvent, 7a-(1,1-dimethoxyethyl)-N-(3 methyl 2 buten-l-yl)-6,7,8,14-tetrahydro- 6,14-endoethanonorthebaine is thereby obtained.

EXAMPLE 74 Preparation of 7a-(1,1-dimethoxyFbutyl)-6,7,8,14- tetrahydro-6,14-endoethanothebaine 7a-butyryl-6,7,8,14-tetrahydro-6,14-endoethanothebaine in ethanol is shaken with a palladium on charcoal catalyst under hydrogen, and 7a-butyryl-6,7,8,14-tetrahydro-6,14- endoethanothebaine is thereby obtained. Following the general procedure of Example 48, 7a-'butyryl-6,7,8,14-

room temperature to give 7a-( 1,1-dimethoxybutyl)-6,7,8, 14-tetra-hydro-6,14-endoethanothebaine.

EXAMPLE 75 Preparation of 7fl-(1,1-dimethoxyethyl)-6,7,8,14-tetrahydro-6,14-endoethen0thebaine Following the general procedure of Example 48, 719- acetyl-6,7,8,l4-tetrahydro 6,14 endoethenothebaine is treated with perchloric acid and trimethyl orthoformate in methanol at room temperature to give 7;8-(1,1-dimethoxyethyl) 6,7,8,14-tetrahydro-6,l4-endoethenothebaine.

EXAMPLE 76 Preparation of N cyano 7B (1,1 dimethoxyethyl)- 6,7,8,14 tetrahydro 6,14 endoethenonorthebaine A solution of cyanogen bromide in chloroform is filtered onto 7,8-(1,1-dimethoxyethyl) 6,7,8,14-tetrahydro- 6,14-endoethenothebaine, chloroform being used for Washing. The mixture is heated under reflux for 26 hours. The cooled mixture is washed with an aqueous sodium bicarbonate solution, washed with water, and dried. The residue obtained by evaporation of the solvent is N- cyano-7B-(1,1 dimethoxyethyl) 6,7,8,14 tetrahydro- 6,1 r-endoethenonorthebaine.

EXAMPLE 77 Preparation of 7;? (1,1 dimethoxyethyl) 6,7,8,14- tetrahydro-6,14-endoethenonorthebaine N-cyano-7fi-(1,l-dimethoxyethyl)-6,7,8,14 tetrahydro- 6,14-endoethenonorthebaine is added to a solution of potassium hydroxide in ethylene glycol heated to ca. C. The reaction mixture is stirred at ca. 165 C. for 15 minutes, and is then cooled and diluted with water. The aqueous solution is extracted with diethyl ether, and the ether extracts are combined, washed with water and dried. The residue obtained by evaporation of the solvent is 7,8- (1,1-dimethoxyethyl)-6,7,8,14-tetrahydro 6,14 endoethenonorthebaine.

EXAMPLE 78 Preparation of N-cyclopropylme-thyl-7fi-( 1,1-dimethoxyethyl) 6,7,8,14 tetrahydro 6,14 endoethenonorthebaine 7fl-(1,1-dimethoxyethyl)-6,7,8,14 tetrahydro 6,14- endoethenonorthebaine in pyridine is added dropwise to a stirred mixture of cy'clopropylcarbonyl chloride and pyridine at 0 C., and the resulting mixture is stirred at 0 C. This is then added dropwise to an aqueous sodium bicarbonate solution with stirring. The precipitate is collected and dried in methylene chloride. The residue obtained upon evaporation of solvent is collected to give N-cyclopropylcarbonyl-7 8-(1,1-dimethoxyethyl) 6,7,8, 14 tetrahydro 6,14 endoethenonorthebaine. Lithium aluminum hydride is added to a solution of N-cyclopropylcarbonyl 7,8 (1,1-dimethoxyethyl) 6,7,8,14- tetrahydro 6,14 endoethenonorthebaine in anhydrous tetrahydrofuran, and the mixture is heated under reflux. A saturated aqueous solution of potassium sodium tartrate is added. The mixture is filtered, and the residue is washed several times with diethyl ether. The combined washings and filtrate are washed with water and dried. Evaporation of the solvent gives N-cyclopropylmethyl- 75-( 1,1 -dimethoxyethyl) 6,7,8,14 tetrahydro 6,14- endoethenonorthebaine.

EXAMPLE 79 Preparation of 7a-acetyl-N-cyclopropylmethyl 6,7,8,14- tetrahydro 6,14 endoethenonorthebaine hydrochloride Following the general procedure of Example 6, 7oc-(1- methoxyvinyl)-N-cyclopropyl'methyl 6,7,8,14 tetrahydro-6,I l-endoethenonorthebaine is dissolved in dilute hydrochloric acid. Extraction of the acidic solution with 25 methylene chloride, followed by isolation of the product, gives 7ot-acetyl-N cyclopropylmethyl 6,7,8,l4-tetrahydro 6,14 endoethenonorthebaine hydrochloride, M.P. 249-250 C. with dec. when crystallized from acetone.

EXAMPLE 80 Preparation of 70t-acetyl-N-cyclopropylmethyl 6,7,8,l4- tetrahydro-6,14-endoethenonororipavine Following the general procedure of Example 6, N- cyclopropylmethyl 7oz (1 methoxyvinyl) 6,7,8,l4- tetrahydro-6,14 endoethenonororipavine is treated with dilute hydrochloric acid. Neutralization with base then gives 7a-acetyl-N-cyclopropylmethyl 6,7,8,l4 tetra-hydro 6,14 endoethenonororipavine, M.P. 208-210 C. when crystallized from methanol.

EXAMPLE 81 Preparation of 70: acetyl 6,7,8,l4 tetrahydro 6,14- endoethanooripavine Following the general procedure of Example 6, 7a-(1- methoxyvinyl) 6,7,8,l4 tetrahydro 6,14-endoethanooripavine is treated with dilute hydrochloric acid. Neutralization with base then gives 7d-acetyl-6,7,8,14-tetrahydro-6, l4-endoethanooripavine.

EXAMPLE 82 Preparation of 7a-acetyl-N cyclopropylmethyl 6,7,8,l4- tetrahydro-6,14-endethanonorthebaine Following the general procedure of Example 6, 7oc(lmethoxyvinyl)-N-cyclopropylmethyl 6,7,8,l4 tetrahydro -'6,14 endoethanonorthebaine is dissolved in dilute hydrochloric acid. Neutralization followed by isolation of the product gives 70: acetyl N cyclopropylmethyl- 6,7,8,l4-tetrahydro 6,14-endoethanonorthebaine.

EXAMPLE 83 Preparation of 7a acetyl-N-cyclopropylmethyl-6,7,8,l4- tetrahydro-6, 14-endo eth'anonororipavine Following the general procedure of Example 6, N- cyclopropylmet-hyl 7a-( l-methoxyvinyl)-6,7,8,14 tetrahydro 6,14 endoethanonororipavine is treated with dilute hydrochloric acid. Neutralization with base then gives 7a-acetyl-N-cyclopropylmethyl 6,7,8,l4-tetrahydro 6,14 endoethanonororipavine.

EXAMPLE 84 Preparation of 75 acetyl 6,7,8,l4 tetrahydro-6,14-

endoethenooripavine Following the general procedure of Example 6, 75-(1- methoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endothenooripavine is treated with dilute hydrochloric acid. Neutralization with base then gives 7;8-acetyl-6,7,8,l4- tetrahydro-6,14 endoethenooripavine.

EXAMPLE 85 Preparation of 713 acetyl-N-cyclopropylmethyl-6,7,8,14- tetrahydro-G,l4-endoethenonorthebaine hydrochloride Preparation of 7a-(2-formyl-l-methoxyvinyl)-6,7,8,14- tetrahydro-6, l4-endoethenothebaine A solution of phosgene in methylene chloride is added rapidly dropwise with stirring to a mixture of dimethyl formamide (dried over molecular sieves) and methylene chloride. The mixture is stirred for a further 15 minutes after the addition is complete. A solution of 7a-(1-methoxyvinyl)-6,7,8,14-tetrahydro 6,14 endothenothebaine in methylene chloride and pyridine is then added in a slow stream and the mixture is stirred for minutes. Aqueous sodium acetate (5%) is then added and the mixture is stirred vigorously for 30 minutes. If necessary, the mixture is adjusted to pH 8 by the addition of aqueous sodium bicarbonate and the layers are separated. The aqueous layer is washed with methylene chloride and is then made strongly alkaline with sodium hydroxide solution (10% The mixture is extracted with ether and the extract is washed with water and dried. Evaporation of solvent followed by crystallization of the residue from acetone-n-hexane gives 7a(2-formyl 1 methoxyvinyl)- 6,7,8,14 tetrahydro 6,14 endoethenothebaine, M.P. 152-153" C.

EXAMPLE 87 Preparation of N-cyclopropylmethyl c (2 formyl-lmethoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethenonorthebaine hydrochloride A solution of phosgene in methylene chloride is added rapidly dropwise with stirring to a mixture of dimethylformamide (dried over molecular sieves) and methylene chloride. The mixture is stirred for a further 15 minutes after the addition is complete. A solution of N-cyclopropylmethyl 7a (l methoxyvinyl)-6,7,8,14-tetrahydro 6,14 endoethenonorthebaine in methylene chloride and pyridine is then added in a slow stream, and the mixture is stirred at room temperature for 45 minutes. Aqueous sodium hydroxide (5%) is then added, and the mixture is stirred vigorously for 30 minutes. The layers are separated and the organic phase is washed with Water and dried. The oil obtained by evaporation of solvent is dissolved in dilute hydrochloric acid (5%), and the solution is washed with ether and extracted with methylene chloride. The extract is dried and evaporated. Acetone is added to cause crystallization and the material is collected with the aid of ether to give N-cyclopropylmethyl- 7a(2-formyl 1 methoxyvinyl)-6,7,8,l4-tetrahydro-6,14- endoethenonorthebaine hydrochloride, M.P. 213-215 C.

EXAMPLE 88 Preparation of 7m(2-formyl-1-methoxyvinyl)-6,7,8,14- tetrahydro-6, l4-endoethenooripavine Following the general procedure of Example 86, 7a- (l-methoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethenooripavine is treated with phosgene-dimethylformamide followed by hydrolysis to give 7a-(2-formyl-lmethoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethenooripavine.

EXAMPLE 89 Preparation of N-cyclopropylmethyl 7a (2 formyl- 1 methoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethenonororipavine Following the general procedure of Example 86, N- cyclopropylmethyl 7a (1 methoxyvinyl) 6,7,8,l4- tetrahydro 6,14 endoethenonororipavine is treated with phosgene-dimethylformamide followed by hydrolysis to give N-cyclopropylmethyl-h-(2-formyl 1 methoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethenonororipavine.

EXAMPLE 90 Preparation of N-cyclopropylmethyl 7oz (2 formyl- 1 methoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethanonororipavine Following the general procedure of Example 86, N- cyclopropylmethyl 7oz (l methoxyvinyl) 6,7,8,l4- tetrahydro 6,14 endoethanonororipavine is treated with phosgene-dimethylformamide followed by hydrolysis to give N-cyclopropylmethyl 70c (2 formyl 1 methoxyvinyl) 6,7,8,l4 tetrahydro 6,14 endoethanonororipavine.

27 EXAMPLE 91 Preparation of N-cyclopropylmethyl 7,6 (2 formyl- 1 methoxyvinyl) 6,7,8,14 tetrahydro 6,14 endoethenororipavine Following the general procedure of Example 86, N- cyclopropylmethyl 7,8 (1 methoxyvinyl) 6,7,8,14- tetrahydro 6,14 endoethenonororipavine is treated with phosgene-dimethylformamide followed by hydrolysis to give N-cyclopropylmethyl 7B (2 formyl 1 methoxyvinyl) 6,7,8,14 tetrahydro 6,14 endoethenonororipavine.

EXAMPLE 92 Preparation of N-cyclopropylmethyl 7a (1 phenyl-- pyrazolyl) 6,7,8,14 tetrahydro 6,14 endoethenonororipavine citrate N-cyclopropylmethyl 70a (2 formyl 1 methoxyvinyl) 6,7,8,14 tetrahydro 6,14 endoethenonororipavine (5 g.), phenylhydrazine hydrochloride (2.5 g.), and acetic acid (100 ml.) are heated on the steam bath for 30 minutes. The mixture is diluted with water and is then made basic with ammonium hydroxide. The material which separates is collected and dried via methylene chloride solution followed by evaporation of solvent to give a glass. A solution of this glass in methylene chloride is passed through a short column of Magnesol. Evaporation of the eluate gives a gum which crystallizes on the addition of ether, and is collected with the aid of ether to give N-cyclopropylmethyl 70 (1 phenyl- S-pyrazolyl) 6,7,8,14 tetrahydro 6,14 endoethenonororipavine (2.8 g., 43%), M.P. l84186 C. The compound has CHaOH max.

242 (inflection point; 6 13,300) and 289 In A hot solution of citric acid (1.5 g.) in ethanol (5 ml.) is added to a hot solution of pyrazole (1.5 g.) in ethanol (15 ml.). N-cyclopropylmethyl-7ot-(l-phenyl-S- pyrazolyl) 6,7,8,14 tetrahydro 6,14 endoethenonororipavine citrate (1.416 g.), M.P. 216 C., dec., separates on standing for several hours. The mother liquor is warmed and ether is added, when a further amount (450 mg.) of product, M.P. 217 C. dec., separates to give a total yield of 98%. The compound has AKBL max.

2.93, 3.85 (broad), 5.74, 5.82 (shoulder), and

nuclear magnetic resonance (d -DMSO) 5 7.50 and 6.13 (pyrazole C 'H and C -H, doublets, J '=1.8 cps), 5.83 and 5.72 (C -H and C -H; doublets, J :9 cps), 4.48 (C -H), 3.08 (C -methoxyl), and 2.70 (CH of citrate; 2 protons or one mole of citric acid per mole of thebaine derivative).

EXAMPLE 93 Preparation of N cyclopropylmethyl 7a-[1-(m-chloro phenyl)-S-pyrazole]-6,7,8,14-tetrahydro 6,14 endoethenonororipavine 28 EXAMPLE 94 Preparation of N cyclopropylmethyl 7a-[1 (m-fiuorophenyl) 5 pyrazolyl]-6,7,8,14-tetrahydro-6,14-endoethenonororipavine Following the general procedure of Example 92, N- cyclopropylmethyl 7a (2 formyl-l-methoxyvinyD- 6,7,8,14 tetrahydro 6,14 endoethenonororipavine is treated 'with m-fiuorophenyl hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7u-[l-(m-fluorophenyl) 5 pyrazolyl] 6,7,8,14-tetrahydro-6,14-endoethenenororipavine.

EXAMPLE 95 Preparation of N cyclopropylmethyl 7a-[l-m-bromophenyl) 5 pyrazolyl] 6,7,8,14-tetrahydro-6,14-endoethenonororipavine Following the general procedure of Example 92, N- cyclopropylmethyl 70c (2 formyl-1-methoxyvinyl)- 6,7,8,14 tetrahydro 6,14 endoethenonororipavine is treated with m-bromophenylhydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a-[l-(m-bromophenyl) 5 pyrazolyl] 6,7,8,14-tetrahydro-6,14-endoethenonororipavine.

EXAMPLE 96 Preparation of N cyclopropylmethyl 7a-[1-(m-tolyl)- 5 pyrazolyl] 6,7,8,14 tetrahydro 6,14 endoethenonororipavine Following the general procedure of Example 92, N- cyclopropylmethyl 7a (2 formyl-1-methoxyviny1)- 6,7,8,14 tetrahydro 6,14 endoethenonororipavine is treated with m-tolylhydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl 7a [l-(m-tolyl)-5-pyrazolyl]-6,7,8,14-tetrahydro-6,14-endoethenonororipavine.

EXAMPLE 97 Preparation of N cyclopropylmethyl-7a-[l-(m-chlorophenyl) 5 pyrazolyl]-6,7,8,14-tetrahydro-6,14-endoethanonororipavine.

Following the general procedure of Example 92, N- cyclopropylmethyl 7a (2 formyl-1-methoxyvinyl)- 6,7,8,14 tetrahydro 6,14 endoethenonororipavine is treated with m-chlorophenyl hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7u-[l-(m-chlorophenyl) 5 pyrazolyl] 6,7,8,14 tetrahydro 6,14-endoethanonororipavine.

EXAMPLE 98 Preparation of N-cyclopropylmethyl 7B [l-(m-chlorophenyl) 5 pyrazolyl] 6,7,8,14-tetrahydro-6,l4-endoethenonororipavine CH O wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkanoyl; R is selected from the group consisting of hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl and lower cycloalkylmethyl; R is selected from the group consisting of hydrogen and alkyl of from 1 to 7 carbon atoms; R is lower alkyl; and Y is selected from the group consisting of etheno and ethano; the nontoxic pharmaceutically acceptable acid-addition salts thereof; and the alkali metal phenolates thereof when R is hydrogen.

2. A compound according to claim 1 wherein R R and R are methyl; R is hydrogen; Y is etheno; and the configuration at the 7 -position is alpha.

3. A compound according to claim 1 wherein R and R are hydrogen; R and R are methyl; Y is etheno; and the configuration at the 7-position is alpha.

4. A compound according to claim 1 wherein R and R are methyl; R is hydrogen; R is cyano; Y is etheno; and the configuration at the 7-position is alpha.

5. A compound according to claim 1 wherein R and R are methyl; R and R are hydrogen; Y is etheno; and the configuration at the 7-position is alpha.

6. A compound according to claim 1 wherein R and R are methyl; R is hydrogen; R is cyclopropylmethyl; Y is etheno; and the configuration at the 7-position is alpha.

7. A compound according to claim 1 wherein R and 30 R are hydrogen; R is methyl; R is cyclopropylmethyl; Y is etheno; and the configuration at the 7-position is alpha.

8. A compound according to claim 1 wherein R R and R are methyl; R is hydrogen; Y is ethano; and the configuration at the 7-position is alpha.

9. A compound according to claim 1 wherein R and R are hydrogen; R is cyclopropylmethyl; R is methyl; Y is ethano; and the configuration at the 7-position is alpha.

10. A compound according to claim 1 wherein R R and R are methyl; R is hydrogen; Y is etheno; and the configuration at the 7-pos-ition is beta.

References Cited UNITED STATES PATENTS 3,285,914 11/1966 Gordon 260285 3,433,791 3/1969 Bentley 260-285 3,442,900 5/1969 Bentley 260285 3,464,992 9/1969 Mayor 260285 3,474,101 10/1969 Bentley 260285 3,474,102 10/1969 Brown 260285 5 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

5 UNITED STATES PATENT OFFICE r CERTIFICATE OF CORRECTION Patent No. 3,560,505 Dated February 2, l9'll John Johnston Brown, Robert Allis Hardy, Jr, a d Inventor-(s) Carol Nora Roth It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[- Column 1, line 35, "ethanol)" should read ethane) Column 2, line 5, "-alkenyl-" should read alken- Column 5, line 25, "reduciton" should read reduction Column 14, line 1, "give" should read gives line 30, "give should read gives Column 18, line 34, "6,15 should read 6,14 Column 21, line 9, "-614,- should read -6,l4- Column 22, line 60, "cycylobutylmethylshould read oyclobutylmethyl- Column 23, line 56,

"-N-3-" should read N-(B- Column 25, line 24, "7dshould read 7(1- line 75, "-endothenothebaine" should read endoethenothebaine Column 27, line 3, "ethenc pavine" should read ethenonororipavine line 61, "pyz zole" should read pyrazolyl Column 28, line 12, "ethenenororipavine" should read ethenonororipavine Column 30, line 12, "B" should read R Signed and sealed this lhth day of September 1971.

(SEAL) Attest:

EDWARD M-FLETGHER,JR- ROBERT GOTTSCHALK attesting Officer Acting Commissioner of Pa 

